The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
Many disease causing microorganisms possess a neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
Very recently the first influenza neuraminidase inhibitor, zanamivir, was approved. However, it can only be administered by inhalation. Therefore, there is a continuing need for improved agents for treatment and/or prevention of influenza infection.
Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains. Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus. Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von Itzstein, et al., European Patent Application No. EP539204, published Apr. 28, 1993 (antiviral agent);
T. Honda; et al., European Patent Application No. EP823428, published Feb. 11, 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. WO98/06712, published Feb. 19, 1998 (sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. WO95/20583, published Aug. 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. WO95/18800, published Jul. 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. WO92/06691, published Apr. 30, 1992 (viral neuraminidase inhibitor);
L. Von Itzstein, et al., U.S. Pat. No. 5,648,379, issued Jul. 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. WO97/32214, published Sep. 4, 1997 (bind to influenza virus neuraminidase active site), and
P. Reece, et al., International Patent Application No. WO98/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility listed after each reference:
Y. Ohira, et al., International Patent Application No. WO98/11083, published Mar. 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721, published Dec. 9, 1998 (antiviral agent); and
B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Pat. No. 5,602,277, issued Feb. 11, 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Pat. No. 5,453,533, issued Sep. 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. WO96/30329, published Oct. 3, 1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Pat. No. 5,763,483, issued Jun. 9, 1998 (neuraminidase inhibitor);
C. Kim, et al., International Patent Application No. WO99/31047, published Jun. 24, 1999 (neuraminidase inhibitor; influenza treatment);
V. Atigadda, et al., J. Med. Chem. 42 2332-2343 (1999) (influenza neuraminidase inhibitor); and
K. Kent, et al., International Patent Application No. 98/07685, published Feb. 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. WO98/17647, published Apr. 30, 1998 discloses piperidine derivatives that are useful as neuraminidase inhibitors.
N. Bischofberger, et al., International Patent Application No. WO96/26933, published Sep. 6, 1996 and N. Bischofberger, et al., International Patent Application No. WO99/14185, published Mar. 25, 1999 disclose various substituted 6-membered ring compounds that are useful as neuraminidase inhibitors.
The following references disclose dihydropyran derivatives that are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. WO97/06157, published Feb. 20, 1997 and U.S. Pat. No. 5,919,819, issued Jul. 6, 1999; and
P. Cherry, et al., International Patent Application No. WO96/36628, published Nov. 21, 1996.
C. Kim, et al., U.S. Pat. No. 5,512,596, issued Apr. 30, 1996 discloses 6-membered aromatic ring derivatives that are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No. WO98/03487, published Jan. 29, 1998 discloses substituted pyridazines that are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No. WO99/06369, published Feb. 11, 1999 discloses piperazine derivatives that are useful as neuraminidase inhibitors.
The following references disclose substituted cyclopentanes that are useful as neuraminidase inhibitors and treatments for influenza:
Y. Babu, et al., International Patent Application No. WO97/47194, published Dec. 18, 1997; and
Y. Babu, et al., International Patent Application No. WO99/33781, published Jul. 8, 1999.
L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid that are useful as Vibrio cholerae sialidase inhibitors.
W. Brouillette, et al., International Patent Application No. WO99/14191, published Mar. 25, 1999, discloses substituted pyrrolidin-2-one compounds that are useful as neuraminidase inhibitors and treatments for influenza.
The following references disclose siastatin B analogs that are useful as neuraminidase inhibitors:
Y. Nishimura, et al., Natural Product Letters 1 3944 (1992); and
Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).
C. Penn, UK Patent Application No. GB2292081, published Feb. 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an influenza vaccine.
An object of the invention is to provide compounds that inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially influenza neuraminidase.
An object of the invention is also to provide compounds that inhibit neuraminidase from both A and B strains of influenza.
Another object of the invention is to provide prophylaxis of influenza infection in humans and other mammals.
Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
Another object of the invention is to provide compounds that exhibit activity against influenza A virus and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
Another object of the invention is to provide a compound that can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
The present invention discloses compounds having Formula I: 
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein R1 is selected from the group consisting of
(a) xe2x80x94CO2H, (b) xe2x80x94CH2CO2H, (c) xe2x80x94SO3H, (d) xe2x80x94CH2SO3H, (e) xe2x80x94SO2H, (f) xe2x80x94CH2SO2H, (g) xe2x80x94PO3H2, (h) xe2x80x94CH2PO3H2, (i) xe2x80x94PO2H, (j) xe2x80x94CH2PO2H, (k) tetrazolyl, (l) xe2x80x94CH2-tetrazolyl, (m) xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(O)2xe2x80x94R11, (n) xe2x80x94CH2C(xe2x95x90O)xe2x80x94NHxe2x80x94S(O)2xe2x80x94R11, (o) xe2x80x94SO2N(Txe2x80x94R11)R12 and (p) xe2x80x94CH2SO2N(Txe2x80x94R11)R12 
wherein T is selected from the group consisting of
(i) a bond, (ii) xe2x80x94C(xe2x95x90O)xe2x80x94, (iii) xe2x80x94C(xe2x95x90O)Oxe2x80x94, (iv) xe2x80x94C(xe2x95x90O)Sxe2x80x94, (v) xe2x80x94C(xe2x95x90O)NR36xe2x80x94, (vi) xe2x80x94C(xe2x95x90S)Oxe2x80x94, (vii) xe2x80x94C(xe2x95x90S)Sxe2x80x94, and (viii) xe2x80x94C(xe2x95x90S)NR36xe2x80x94,
R11 is selected from the group consisting of
(i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl)alkyl, (v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (viii) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl, (xii) heterocyclic, (xiii) (heterocyclic)alkyl and (xiii) (xiv) (heterocyclic)alkenyl; and
R12 and R36 are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of
(a) xe2x80x94C(xe2x95x90O)xe2x80x94N(R*)xe2x80x94, (b) xe2x80x94N(R*)xe2x80x94C(xe2x95x90O)xe2x80x94, (c) xe2x80x94C(xe2x95x90S)xe2x80x94N(R*)xe2x80x94, (d) xe2x80x94N(R*)xe2x80x94C(xe2x95x90S)xe2x80x94, (e) xe2x80x94N(R*)xe2x80x94SO2xe2x80x94, and (f) xe2x80x94SO2xe2x80x94N(R*)xe2x80x94 wherein R* is hydrogen, C1-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2xe2x80x94Xxe2x80x94 is 
wherein Y1 is xe2x80x94CH2, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from the group consisting of
(a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) xe2x80x94Zxe2x80x94R14 
wherein Z is
(i) xe2x80x94C(R37a)(R37b)xe2x80x94, (ii) xe2x80x94C(R47)xe2x95x90C(R48)xe2x80x94, (iii) xe2x80x94Cxe2x89xa1Cxe2x80x94, (iv) xe2x80x94C(xe2x95x90O)xe2x80x94,
(v) xe2x80x94C(xe2x95x90S)xe2x80x94, (vi) xe2x80x94C(xe2x95x90NR15)xe2x80x94, (vii) xe2x80x94C(R37a)(OR37c)xe2x80x94, (viii) xe2x80x94C(R37a)(SR37c)xe2x80x94,
(ix) xe2x80x94C(R37a)(N(R37b)(R37c))xe2x80x94, (x) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94,
(xi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37c)xe2x80x94, (xii) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)xe2x80x94,
(xiii) xe2x80x94C(R37a)(R37b)xe2x80x94N(OH)xe2x80x94, (xiv) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94,
(xv) xe2x80x94C(R37a)(R37b)xe2x80x94S(O)xe2x80x94, (xvi) xe2x80x94C(R37a)(R37b)xe2x80x94S(O)2xe2x80x94,
(xvii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94, (xviii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94,
(xix) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90NR15)xe2x80x94, (xx) C(R37a)(OR37c)xe2x80x94C(xe2x95x90O)xe2x80x94,
(xxi) xe2x80x94C(R37a)(SR37c)xe2x80x94C(xe2x95x90O)xe2x80x94, (xxii) C(R37a)(OR37c)xe2x80x94C(xe2x95x90S)xe2x80x94,
(xxiii) xe2x80x94C(R37a)(SR37c)xe2x80x94C(xe2x95x90S)xe2x80x94, (xxiv) xe2x80x94C(xe2x95x90O)xe2x80x94C(R37a)(OR37c)xe2x80x94,
(xxv) xe2x80x94C(xe2x95x90O)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxvi) xe2x80x94C(xe2x95x90S)xe2x80x94C(R37a)(OR37c)xe2x80x94,
(xxvii) xe2x80x94C(xe2x95x90S)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxviii) xe2x80x94C(R37a)(OR37c)xe2x80x94C(R37a)(OR37c)xe2x80x94,
(xxix) xe2x80x94C(R37a)(SR37c)xe2x80x94C(R37a)(OR37c)xe2x80x94,
(xxx) xe2x80x94C(R37a)(OR37c)xe2x80x94C(R37a)(SR37c)xe2x80x94,
(xxxi) xe2x80x94C(R37a)(SR37c)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxxii) xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94,
(xxxiii) xe2x80x94C(xe2x95x90S)xe2x80x94C(xe2x95x90S)xe2x80x94, (xxxiv) xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (xxxv) xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94,
(xxxvi) xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (xxxvii) xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (xxxviii) xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94,
(xxxix) xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xl) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94,
(xli) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xlii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94,
(xliii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xliv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94,
(xlv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (xlvi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94,
(xlvii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94, (xlviii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94,
(xlix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94, (l) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94,
(li) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94, (lii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94,
(liii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94,
(liv) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94,
(lv) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94,
(lvi)xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94,
(lvii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94,
(lviii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94,
(lix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94,
(lx) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94,
(lxi) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (lxii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94,
(lxiii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (lxiv) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94,
(lxv) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (lxvi) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94,
(lxvii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (lxviii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94,
(lxix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94 or (lxx) xe2x80x94C(R37a)(R37b)xe2x80x94C(R37a)(OR37c)xe2x80x94;
R14 is
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) thiol-substituted alkyl, (vi) R37cxe2x80x94O-substituted alkyl,
(vii) R37cxe2x80x94S-substituted alkyl, (viii) aminoalkyl,
(ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-substituted alkyl,
(xi) R37aOxe2x80x94(Oxe2x95x90)C-substituted alkyl, (xii) R37aSxe2x80x94(Oxe2x95x90)C-substituted alkyl, (xiii) R37aOxe2x80x94(Sxe2x95x90)C-substituted alkyl,
(xiv) R37aSxe2x80x94(Sxe2x95x90)C-substituted alkyl,
(xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl, (xvi) cyanoalkyl,
(xvi) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl,
(xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,
(xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,
(xxv) (cycloalkenyl)alkyl,
(xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl,
(xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,
(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,
(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,
with the proviso that R14 is other than hydrogen when Z is
xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94 or xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94;
R37a, R37b, R47, and R48 at each occurrence are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl,
(viii) C2-C12 alkynyl, (ix) cycloalkyl,
(x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl,
(xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)alkenyl,
(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,
(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,
(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and
(xxiv) (heterocyclic)alkynyl;
R37c at each occurrence is independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl,
(v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl,
(viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl,
(xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl,
(xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl,
(xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic,
(xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,
(xxii) (heterocyclic)alkynyl, (xxiii) xe2x80x94C(xe2x95x90O)xe2x80x94R4, (xxiv) xe2x80x94C(xe2x95x90S)xe2x80x94R14,
(xxv) xe2x80x94S(O)2xe2x80x94R14 and (xxvi) hydroxyalkyl;
or when Z is xe2x80x94C(R37a)(R37b)xe2x80x94N(R37c)xe2x80x94, then N(R37c) and R14 when taken together are an azido group;
or when Z is xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)xe2x80x94, then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is xe2x80x94C(R37a)(R37b)xe2x80x94, xe2x80x94C(R37a)(OR37c)xe2x80x94, xe2x80x94C(R37a)(SR37c) or xe2x80x94C(R37a)(N(R37a)(R37c))xe2x80x94, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring or then OR37c or SR37c or N(R37c) and R14 and the carbon atom to which they are bonded when taken together form a heterocyclic ring containing an O, S or N atom, respectively, and having from 4 to 8 ring atoms;
R15 is selected from the group consisting of
(i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C1-C12 alkyl, (v) haloalkyl,
(vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl,
(ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl,
(xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl,
(xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic,
(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R5 is selected from the group consisting of
(a) hydrogen, (b) xe2x80x94CH(R38)2, (c) xe2x80x94Oxe2x80x94R40, (d) C2C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) xe2x80x94C(xe2x95x90Q1)xe2x80x94R17, and (h) xe2x80x94N(R19)2 
wherein Q1 is O, S, or N(R15);
R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl,
(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,
(viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl,
(xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl,
(xv) heterocyclic, (xvi) (heterocyclic)alkyl and
(xvii) (heterocyclic)alkenyl;
Y is selected from the group consisting of
(a) hydrogen, (b) C1-C5 alkyl, (c) C1-C5 haloalkyl, (d) C2-C5 alkenyl, (e) C2-C5 haloalkenyl, (f) C2-C5 alkynyl, (g) C3-C5 cycloalkyl, (h) C3-C5 cycloalkyl-C1-to-C3-alkyl, (i) C5 cycloalkenyl, (j) C5 cycloalkenyl-C1-to-C3-alkyl, (k) C5 cycloalkenyl-C2-to-C3-alkenyl, (l) xe2x80x94(CHR39)nOR20, (m) xe2x80x94CH(OR2)xe2x80x94CH2(OR20), (n) xe2x80x94(CHR39)nSR21, (o) xe2x80x94(CHR39)nCN, (p) xe2x80x94(CHR39)nN3, (q) phenyl, (r) halo-substituted phenyl, (s) xe2x80x94(CHR39)nC(xe2x95x90Q2)R22, (t) xe2x80x94(CHR39)nN(xe2x95x90Q3), (u) xe2x80x94N(O)xe2x95x90CHCH3, (v) xe2x80x94(CHR39)nNR23R24, (w) halo and (x) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42;
R20 at each occurrence is independently
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl, (xi) C2-C3 haloalkenyl, (xii) amino, (xiii) xe2x80x94NHCH3, (xiv) xe2x80x94N(CH3)2, (xv) xe2x80x94NHCH2CH3, (xvi) xe2x80x94N(CH3)(CH2CH3), (xvii) xe2x80x94N(CH2CH3)2 or
(xviii) xe2x80x94N(xe2x95x90CH2);
R21 is
hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
R22 is
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,
(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio,
(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl,
(xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) xe2x80x94N(R28a)(R28b),
(xxiii) xe2x80x94CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl,
(xxvi) thiolmethyl, (xxvii) xe2x80x94NHNH2, (xxviii) xe2x80x94N(CH3)NH2 or
(xxix) xe2x80x94NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of
(i) hydrogen, (ii) C1-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) xe2x80x94C(xe2x95x90Q4)xe2x80x94R30, (v) xe2x80x94OR31, and (vi) xe2x80x94N(R32)2;
wherein Q4 is O, S, or N(R33);
R25 is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94CN, or xe2x80x94NO2;
R26 group is hydrogen, methyl or ethyl;
R28a hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94NHCH3, xe2x80x94N(CH3)2, methoxy, ethoxy, or xe2x80x94CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, xe2x80x94OR34, xe2x80x94SR34, xe2x80x94N(R35)2, xe2x80x94NHOH, xe2x80x94NHNH2, xe2x80x94N(CH3)NH2, or xe2x80x94N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94CN, or xe2x80x94NO2;
R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94C3H7, xe2x80x94OCH3, xe2x80x94SCH3, xe2x80x94Oxe2x80x94C2H5, and xe2x80x94Sxe2x80x94C2H5,
and with the proviso that when R3 and R4 are each hydrogen, then Y is other than hydrogen;
R6 and R7 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (i) (cycloalkenyl)alkenyl, Q) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl and (o) (heterocyclic)alkenyl; and
R8, R9, and R10 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
Preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula IIA: 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 and R4 are not both the same.
More preferred compounds of the invention are enantiomerically enriched compounds having the absolute sterochemistry depicted by Formula IIB: 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 and R4 are not both the same.
Other preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula IIIA: 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 and R4 are not both the same.
Other more preferred compounds of the invention are enantiomerically enriched compounds having the absolute sterochemistry depicted by Formula 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 and R4 are not both the same.
Other preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is defined as above;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen, fluoro or loweralkyl;
R10 is hydrogen, fluoro or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3, xe2x80x94NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as above.
More preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is defined as above;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3, xe2x80x94NR23R24 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, R23, R24, Q2 and Q3 are defined as above.
Even more preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is defined as above; xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C1-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
wherein Y1 is CH2xe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O) or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
More highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are hydrogen independently hydrogen or loweralkyl;
R8 and R9 are hydrogen independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Even more highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other even more highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (b) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) xe2x80x94C(xe2x95x90O)xe2x80x94R14, (h) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 or (i) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)xe2x80x94R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Most highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is
(i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is
(i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and
R37c is
(i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
R37a is
loweralkyl or loweralkenyl; and
R37c is
hydrogen, C1-C3 loweralkyl or allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or R2xe2x80x94SO2NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
R37a is
loweralkyl or loweralkenyl; and
R37c is
hydrogen, C1-C3 loweralkyl or allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl.
Preferred substituents R1 include xe2x80x94CO2H or esters or prodrugs thereof. Preferred esters include C1-C6 loweralkyl esters, cycloalkyl esters (for example, cyclopropyl ester, cyclohexyl ester and the like), cycloalkylalkyl esters, aryl esters (for example, phenyl ester, 2-methylphenyl ester and the like), arylalkyl esters (for example, benzyl ester, phenylethyl ester and the like), haloalkyl esters (for example, 2,2,2-trichloroethyl ester and the like), heterocyclic esters (for example, N-methylpiperazin-4-yl ester and the like), (heterocyclic)alkyl esters (for example, pyridyl methyl ester, pyridylethyl ester, N-methylpiperazin-4-ylmethyl ester, piperidin-1-ylmethyl ester, morpholin-4-ylmethyl ester, 2-(piperidin-1-yl)ethyl ester, 2-(morpholin-4-yl)ethyl ester, 2(-N-methylpiperazin-4-yl)ethyl ester, 1,1-dimethyl-2-(piperidin-1-yl)ethyl ester, 1,1-dimethyl-2-(morpholin-4-yl)ethyl ester, 1,1-dimethyl-2-(N-methylpiperazin-4-yl)ethyl ester, phthalidylmethyl ester and the like), di-loweralkylaminoalkyl esters (for example, 2-N,N-dimethylaminoethyl ester, 2-N,N-diethylaminoethyl ester and the like), acyloxyalkyl esters (for example, t-butylcarbonyloxymethyl ester and the like), alkoxycarbonyloxyalkyl esters (for example, t-butyloxycarbonyloxymethyl ester and the like), di-loweralkylaminocarbonylalkyl esters (for example, N,N-dimethylaminocarbonylmethyl ester, N,N-diethylaminocarbonylmethyl ester and the like), acylalkyl esters (for example, t-butylcarbonylmethyl ester and the like), (heterocyclic)carbonylalkyl esters (for example, piperidin-1-ylcarbonylmethyl ester, morpholin-4-ylcarbonylmethyl ester, N-methylpiperazin-4-ylcarbonylmethyl ester and the like), di-loweralkylaminocarbonyloxyalkyl esters (for example, N,N-dimthylaminocarbonyloxymethyl ester, N,N-diethylaminocarbonyloxymethyl ester, N-t-butyl-N-methylaminocarbonyloxymethyl ester and the like), alkoxycarbonylalkyl esters (for example, ethoxycarbonylmethyl ester, isopropoxycarbonylmethyl ester and the like), (heterocyclic)carbonyloxyalkyl esters (for example, pyridylcarbonyloxymethyl ester and the like) and the like. Preferred substituents R1 also include xe2x80x94S(O)2NHC(xe2x95x90O)R11 wherein R11 is defined as above.
Most highly preferred substituents R1 include xe2x80x94CO2H or esters or prodrugs thereof. Most highly preferred esters include C1-C6 loweralkyl esters, cycloalkyl esters, cycloalkylalkyl esters or substituted or unsubstituted benzyl esters.
Preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
wherein Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
More preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
wherein Y1 is xe2x80x94CH2xe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.
Even more preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl.
More highly preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl.
Even more highly preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C2 loweralkyl or halo C1-C2 loweralkyl, and especially, CH3xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, CF3xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, CH3xe2x80x94SO2xe2x80x94NHxe2x80x94 or CF3xe2x80x94SO2xe2x80x94NHxe2x80x94.
Preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as most broadly defined previously herein and wherein one of R3 and R4 is other than hydrogen.
More highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes heterocyclic or xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as most broadly defined previously herein.
Even more highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes
(a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) xe2x80x94C(xe2x95x90O)xe2x80x94R14, (h) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 or (i) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)xe2x80x94R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl.
Most highly preferred, substituent R4 is hydrogen and R3 includes
(a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(R37c)xe2x80x94R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes
(a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is
(i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes
xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
R37a is loweralkyl or loweralkenyl; and
R37c is hydrogen, C1-C3 loweralkyl or allyl, and especially, wherein R37c is hydrogen or methyl.
Preferred substituents R5 include hydrogen or loweralkyl. Most highly preferred, R5 is hydrogen.
Preferred substituents R6 and R7 include independently hydrogen and loweralkyl. Most highly preferred, R6 and R7 are hydrogen.
Preferred substituents R8, R9 and R10 include independently hydrogen, fluoro and loweralkyl. Most highly preferred, R8, R9 and R10 are hydrogen.
Preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3, xe2x80x94NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as above.
More preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3, xe2x80x94NR23R24 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, R23, R24, Q2 and Q3 are defined as above.
Even more preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y include:
xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHF, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94CHxe2x95x90CHxe2x80x94CF3, xe2x80x94CHxe2x95x90CHCl, xe2x80x94CHxe2x95x90CHBr, xe2x80x94CHxe2x95x90CF2, xe2x80x94CHxe2x95x90CF(CH3), xe2x80x94CHxe2x95x90CF(CF3), xe2x80x94CHxe2x95x90CFCl, xe2x80x94CHxe2x95x90CFBr, xe2x80x94CHxe2x95x90C(CH3)2, xe2x80x94CHxe2x95x90C(CH3)(CF3), xe2x80x94CHxe2x95x90CCl(CH3), xe2x80x94CHxe2x95x90CBr(CH3), xe2x80x94CHxe2x95x90C(CF3)2, xe2x80x94CHxe2x95x90CCl(CF3), xe2x80x94CHxe2x95x90CBr(CF3), xe2x80x94CHxe2x95x90CCl2, xe2x80x94CHxe2x95x90CClBr, xe2x80x94CFxe2x95x90CH2, xe2x80x94CFxe2x95x90CHF, xe2x80x94CFxe2x95x90CHxe2x80x94CH3, xe2x80x94CFxe2x95x90CHxe2x80x94CF3, xe2x80x94CFxe2x95x90CHCl, xe2x80x94CFxe2x95x90CHBr, xe2x80x94CFxe2x95x90CF2, xe2x80x94CFxe2x95x90CF(CH3), xe2x80x94CFxe2x95x90CF(CF3), xe2x80x94CFxe2x95x90CFCl, xe2x80x94CFxe2x95x90CFBr, xe2x80x94CFxe2x95x90C(CH3)2, xe2x80x94CFxe2x95x90C(CH3)(CF3), xe2x80x94CFxe2x95x90CCl(CH3), xe2x80x94CFxe2x95x90CBr(CH3), xe2x80x94CFxe2x95x90C(CF3)2, xe2x80x94CFxe2x95x90CCl(CF3), xe2x80x94CFxe2x95x90CBr(CF3), xe2x80x94CFxe2x95x90CCl2, xe2x80x94CFxe2x95x90CClBr, xe2x80x94C(CH3)xe2x95x90CH2, xe2x80x94C(CH3)xe2x95x90CHF, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH3, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CF3, xe2x80x94C(CH3)xe2x95x90CHCl, xe2x80x94C(CH3)xe2x95x90CHBr, xe2x80x94C(CH3)xe2x95x90CF2, xe2x80x94C(CH3)xe2x95x90CF(CH3), xe2x80x94C(CH3)xe2x95x90CF(CF3), xe2x80x94C(CH3)xe2x95x90CFCl, xe2x80x94C(CH3)xe2x95x90CFBr, xe2x80x94C(CH3)xe2x95x90C(CH3)2, xe2x80x94C(CH3)xe2x95x90C(CH3)(CF3), xe2x80x94C(CH3)xe2x95x90CCl(CH3), xe2x80x94C(CH3)xe2x95x90CBr(C H3), xe2x80x94C(C H3)xe2x95x90C(CF3)2, xe2x80x94C(CH3)xe2x95x90CCl(CF3), xe2x80x94C(CH3)xe2x95x90CBr(CF3), xe2x80x94C(CH3)xe2x95x90CCl2, xe2x80x94C(CH3)xe2x95x90CClBr, xe2x80x94C(CF3)xe2x95x90CH2, xe2x80x94C(CF3)xe2x95x90CHF, xe2x80x94C(CF3)xe2x95x90CHxe2x80x94CH3, xe2x80x94C(CF3)xe2x95x90CHxe2x80x94CF3, xe2x80x94C(CF3)xe2x95x90CHCl, xe2x80x94C(CF3)xe2x95x90CHBr, xe2x80x94C(CF3)xe2x95x90CF2, xe2x80x94C(CF3)xe2x95x90CF(CH3), xe2x80x94C(CF3)xe2x95x90CF(CF3), xe2x80x94C(CF3)xe2x95x90CFCl, xe2x80x94C(CF3)xe2x95x90CFBr, xe2x80x94C(CF3)xe2x95x90C(CH3)2, xe2x80x94C(CF3)xe2x95x90C(CH3)(CF3), xe2x80x94C(CF3)xe2x95x90CCl(CH3), xe2x80x94C(CF3)xe2x95x90CBr(CH3), xe2x80x94C(CF3)xe2x95x90C(CF3)2, xe2x80x94C(CF3)xe2x95x90CCl(CF3), xe2x80x94C(CF3)xe2x95x90CBr(CF3), xe2x80x94C(CF3)xe2x95x90CCl2, xe2x80x94C(CF3)xe2x95x90CClBr, xe2x80x94CClxe2x95x90CH2, xe2x80x94CClxe2x95x90CHF, xe2x80x94CClxe2x95x90CHxe2x80x94CH3, xe2x80x94CClxe2x95x90CHxe2x80x94CF3, xe2x80x94CClxe2x95x90CHCl, xe2x80x94CClxe2x95x90CHBr, xe2x80x94CClxe2x95x90CF2, xe2x80x94CClxe2x95x90CF(CH3), xe2x80x94CClxe2x95x90CF(CF3), xe2x80x94CClxe2x95x90CFCl, xe2x80x94CClxe2x95x90CFBr, xe2x80x94CClxe2x95x90C(CH3)2, xe2x80x94CClxe2x95x90C(CH3)(C F3), xe2x80x94CClxe2x95x90CCl(CH3), xe2x80x94CClxe2x95x90CBr(CH3), xe2x80x94CClxe2x95x90C(CF3)2, xe2x80x94CClxe2x95x90CCl(CF3), xe2x80x94CClxe2x95x90CBr(CF3), xe2x80x94CClxe2x95x90CCl2, xe2x80x94CClxe2x95x90CClBr, xe2x80x94CHxe2x95x90CHxe2x80x94CH2CH3, xe2x80x94CHxe2x95x90CFxe2x80x94CH2CH3, xe2x80x94CFxe2x95x90CHxe2x80x94CH2CH3, xe2x80x94CFxe2x95x90CFxe2x80x94CH2CH3, xe2x80x94CHxe2x95x90C(CH3)(CH2CH3), xe2x80x94CFxe2x95x90C(CH3)(CH2CH3), xe2x80x94CHxe2x95x90CCl(CH2CH3), xe2x80x94CFxe2x95x90CCl(CH2CH3), xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH2CH3, xe2x80x94C(CH3)xe2x95x90CFxe2x80x94CH2CH3, xe2x80x94CClxe2x95x90CHxe2x80x94CH2CH3, xe2x80x94CClxe2x95x90CFxe2x80x94CH2CH3, xe2x80x94C(CH2CH3)xe2x95x90CH2, xe2x80x94C(CH2CH3)xe2x95x90CHF, xe2x80x94C(CH2CH3)xe2x95x90CF2, xe2x80x94C(CH2CH3)xe2x95x90CHxe2x80x94CH3, xe2x80x94C(CH2CH3)xe2x95x90CFxe2x80x94CH3, xe2x80x94C(CH2CH3)xe2x95x90CHxe2x80x94Cl, xe2x80x94C(CH2CH3)xe2x95x90CFCl.
Representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinyl, thiadiazolyl, thiadiazolinyl, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl.
More highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2.
Most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, NH2, xe2x80x94NHC(xe2x95x90NH)NH2, especially, cis-propenyl.
Preferred definitions for the substituents in the compounds of the invention also apply to the intermediates disclosed herein that are useful in the preparation of the compounds of the invention.
Preferred compounds of the invention include compounds having the indicated relative stereochemistry selected from the group consisting of:
(xc2x1)-(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
(xc2x1)-(2R,3R,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xe2x88x92)-(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)butyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3(cis-propen-1-yl)-pyrrolidine-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen 1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S,3xe2x80x2R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2S,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2 1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Other preferred compounds of the invention include enantiomerically enriched compounds having the indicated absolute stereochemistry selected from the group consisting of:
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
(2R,3R,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S,3xe2x80x2R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,lxe2x80x2S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylic Acid;
(2S,3R,5R,1xe2x80x2S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
More preferred compounds of the invention include compounds having the indicated relative stereochemistry selected from the group consisting of:
(xc2x1)-(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
(xc2x1)-(2R,3R,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xe2x88x92)-(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3R,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Other more preferred compounds of the invention include enantiomerically enriched compounds having the indicated absolute stereochemistry selected from the group consisting of:
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
(2R,3R,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xe2x88x92)-(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3R,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S,3xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Even more preferred compounds of the invention include compounds having the indicated relative stereochemistry selected from the group consisting of:
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(xc2x1)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Other even more preferred compounds of the invention include enantiomerically enriched compounds having the indicated absolute stereochemistry selected from the group consisting of:
(xe2x88x92)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(xe2x88x92)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Most highly preferred compounds of the invention include enantiomerically enriched esters or prodrugs of compounds having the indicated absolute stereochemistry selected from the group consisting of:
(xe2x88x92)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; and
(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt thereof.
Most highly preferred compounds of the invention also include enantiomerically enriched esters or prodrugs of the compound having the indicated absolute stereochemistry:
(xe2x88x92)-(2R,3S,5R,1xe2x80x2R,2xe2x80x2S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
or a pharmaceutically acceptable salt thereof.
The term xe2x80x9cacid protecting groupxe2x80x9d as used herein refers to groups used to protect acid groups (for example, xe2x80x94CO2H, xe2x80x94SO3H, xe2x80x94SO2H, xe2x80x94PO3H2, xe2x80x94PO2H groups and the like) against undesirable reactions during synthetic procedures. Commonly used acid protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991) which is incorporated herein by reference. Most frequently, such acid protecting groups are esters.
Such esters include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
arylalkyl esters including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.
Preferred acid protecting groups are loweralkyl esters.
The term xe2x80x9cactivated carboxylic acid groupxe2x80x9d as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,Nxe2x80x2-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
The term xe2x80x9cacylxe2x80x9d as used herein, refers to groups having the formula xe2x80x94C(xe2x95x90O)xe2x80x94R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups as R95 are loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.
The term xe2x80x9cacylalkylxe2x80x9d as used herein refers to an acyl group appended to an alkyl radical. Representative examples of acylalkyl groups include acetylmethyl, acetylethyl, propionylmethyl, propionylethyl and the like.
The term xe2x80x9cacylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.
The term xe2x80x9cacyloxyalkylxe2x80x9d as used herein refers to an acyloxy group (i.e., R95xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R95 is hydrogen or an alkyl group) which is appended to an alkyl radical. Representative examples of acyloxyalkyl include acetyloxymethyl, acetyloxyethyl, propioyloxymethyl, propionyloxyethyl and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term xe2x80x9clower alkenylxe2x80x9d refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
The term xe2x80x9calkenylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term xe2x80x9clower alkenylenexe2x80x9d refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94OR81 where R81 is an alkenyl group.
The term xe2x80x9calkoxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyl groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94Oxe2x80x94R96xe2x80x94Oxe2x80x94R97 wherein R97 is loweralkyl, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein, refers to groups having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94R80, where R80 is an alkoxy group.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein, refers to groups having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94R79, appended to the parent molecular moiety through an alkylene linkage, where R79 is an alkoxy group.
The term xe2x80x9calkoxycarbonyloxyalkylxe2x80x9d as used herein refers to an alkoxycarbonyloxy group (i.e., R80xe2x80x94C(O)xe2x80x94O wherein R80 is an alkoxy group) appended to an alkyl radical. Representative examples of alkoxycarbonyloxyalkyl include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term xe2x80x9cloweralkylxe2x80x9d refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, xe2x80x94N(R27)xe2x80x94 and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term xe2x80x9calkylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94NHR91 wherein R91 is an alkyl group. Preferred R91 groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
The term xe2x80x9calkylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term xe2x80x9clower alkylenexe2x80x9d refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (xe2x80x94CH2xe2x80x94), 1,2-ethylene (xe2x80x94CH2CH2xe2x80x94), 1,1-ethylene (xe2x80x94CH(CH3)xe2x80x94), 1,3-propylene (xe2x80x94CH2CH2CH2xe2x80x94), 2,2-dimethylpropylene (xe2x80x94CH2C(CH3)2CH2xe2x80x94), and the like. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, xe2x80x94N(R27)xe2x80x94 and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94SO2xe2x80x94R78, where R78 is an alkyl group. Preferred groups R78 are loweralkyl groups.
The term xe2x80x9calkylsulfonylaminoxe2x80x9d as used herein refers to the group having the formula, xe2x80x94SO2xe2x80x94R7, appended to the parent molecular moiety through an amino linkage (xe2x80x94NHxe2x80x94), where R77 is an alkyl group. Preferred groups R77 are loweralkyl groups.
The term xe2x80x9calkynylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term xe2x80x9clower alkynylxe2x80x9d refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9calkynylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term xe2x80x9clower alkynylenexe2x80x9d refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1Cxe2x80x94, and the like.
The term xe2x80x9caminoalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended an amino (xe2x80x94NH2) group.
The term xe2x80x9carylxe2x80x9d as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (xe2x95x90O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, NH2C(xe2x95x90O)xe2x80x94, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted (heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and xe2x80x94SO3H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
The term xe2x80x9c(aryl)alkenylxe2x80x9d refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.
The term xe2x80x9c(aryl)alkylxe2x80x9d refers to a loweralkyl group having appended thereto an aryl group. Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94Oxe2x80x94R76 where R76 is an arylalkyl group.
The term xe2x80x9c(aryl)alkynylxe2x80x9d refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94Oxe2x80x94R72, where R72 is an aryl group.
The term xe2x80x9ccarbamoylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94NH2.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein, refers to the group having the formula, xe2x80x94R64xe2x80x94COOH, where R64 is a lower alkylene group.
The term xe2x80x9ccyanoalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a cyano group (xe2x80x94CN).
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substituents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term xe2x80x9c(cycloalkenyl)alkenylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
The term xe2x80x9c(cycloalkenyl)alkylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
The term xe2x80x9c(cycloalkenyl)alkynylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term xe2x80x9c(cycloalkyl)alkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term xe2x80x9c(cycloalkyl)alkenylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkenyl radical. Representative examples of (cycloalkyl)alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.
The term xe2x80x9c(cycloalkyl)alkynylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94N(R90)2 wherein each R90 is independently a lower alkyl group. Representative examples of dialkylamino include dimethylamino, diethylamino, N-methyl-N-isopropylamino and the like.
The term xe2x80x9cdialkylaminoalkylxe2x80x9d as used herein refers to a dialkylamino group appended to an alkyl radical. Representative examples of dialkylaminoalkyl include dimethylaminomethyl, dimethylaminoethyl, N-methyl-N-ethylaminoethyl and the like.
The term xe2x80x9cdialkylaminocarbonylalkylxe2x80x9d as used herein refers to a C(O)xe2x80x94N(R90)2 group (wherein each R90 is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonylalkyl include dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, N-methyl-N-ethylaminocarbonylethyl and the like.
The term xe2x80x9cdialkylaminocarbonyloxyalkylxe2x80x9d as used herein refers to a xe2x80x94Oxe2x80x94C(O)xe2x80x94N(R90)2 group (wherein each R90 is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonyloxyalkyl include dimethylaminocarbonyloxymethyl, diethylaminocarbonyloxymethyl, N-methyl-N-ethylaminocarbonyloxyethyl and the like.
The term xe2x80x9cenantiomerically enrichedxe2x80x9d as used herein refers to a compound which comprises unequal amounts of the enantiomers of an enantiomeric pair. In other words, an enantiomerically enriched compound comprises more than 50% of one enantiomer of an enantiomeric pair and less than 50% of the other enantiomer of the enantiomeric pair. Preferably, a compound that is enantiomerically enriched comprises predominantly one enantiomer of an enantiomeric pair. Preferably, an enantiomerically enriched compound comprises greater than 80% of one enantiomer of an enantiomeric pair and less than 20% of the other enantiomer of the enantiomeric pair. More preferably, an enantiomerically enriched compound comprises greater than 90% of one enantiomer of an enantiomeric pair and less than 10% of the other enantiomer of the enantiomeric pair. Even more preferably, an enantiomerically enriched compound comprises greater than 95% of one enantiomer of an enantiomeric pair and less than 5% of the other enantiomer of the enantiomeric pair. Even more highly preferably, an enantiomerically enriched compound comprises greater than 97% of one enantiomer of an enantiomeric pair and less than 3% of the other enantiomer of the enantiomeric pair. Yet even more highly preferably, an enantiomerically enriched compound comprises greater than 98% of one enantiomer of an enantiomeric pair and less than 2% of the other enantiomer of the enantiomeric pair. Most preferably, an enantiomerically enriched compound comprises greater than 99% of one enantiomer of an enantiomeric pair and less than 1% of the other enantiomer of the enantiomeric pair.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalidexe2x80x9d as used herein refers to F, Cl, Br or I.
The term xe2x80x9chaloalkenylxe2x80x9d as used herein refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2-difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene and the like.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
The term xe2x80x9chaloalkylxe2x80x9d as used herein, refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl, 1,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula 
where X* is xe2x80x94CH2 or xe2x80x94Oxe2x80x94 and Y1 is xe2x80x94C(O)xe2x80x94 or [xe2x80x94C(R92)2xe2x80x94]v where R92 is hydrogen or C1-C4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.
The term xe2x80x9c(heterocyclic)alkenylxe2x80x9d as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
The term xe2x80x9c(heterocyclic)alkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94OR68, where R68 is a (heterocyclic)alkyl group.
The term xe2x80x9c(heterocyclic)alkylxe2x80x9d as used herein refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
The term xe2x80x9c(heterocyclic)alkynylxe2x80x9d as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
The term xe2x80x9c(heterocyclic)carbonylalkylxe2x80x9d as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyl group. Representative examples of (heterocyclic)carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
The term xe2x80x9c(heterocyclic)carbonyloxyalkylxe2x80x9d as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyloxy group (i.e., xe2x80x94C(O)xe2x80x94Oxe2x80x94). Representative examples of (heterocyclic)carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
The term xe2x80x9c(heterocyclic)oxyxe2x80x9d as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (xe2x80x94Oxe2x80x94).
The term xe2x80x9chydroxy protecting groupxe2x80x9d, xe2x80x9chydroxyl protecting groupxe2x80x9d or xe2x80x9cxe2x80x94OH protecting groupxe2x80x9d as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991) which is incorporated by reference herein. Such hydroxy protecting groups include:
methyl ether;
substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
benzyl ether;
substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94R65xe2x80x94OH, where R65 is an alkylene group
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-Sxe2x80x94), triphenylmethylsulfenyl (trityl-Sxe2x80x94) and the like; sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)xe2x80x94), t-butylsulfinyl (t-Buxe2x80x94S(O)xe2x80x94) and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like; p-methoxyphenyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to groups having the formula xe2x80x94SR98 wherein R98 is an alkyl group. Preferred groups R98 are loweralkyl groups.
The term xe2x80x9cthio-substituted alkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a thiol group (xe2x80x94SH).
As used herein, the terms xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By xe2x80x9csubstantially freexe2x80x9d is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
In addition, solvates and hydrates of the compounds of Formula I, IIA, IIB, IIIA or IIIB are meant to be included in this invention.
When any variable (for example R1, R2, R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I, IIA, IIB, IIIA or IIIB or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
This invention is intended to encompass compounds having Formula I, IIA, IIB, IIIA or IIIB when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
Compounds of the invention can be prepared according to the methods described in Schemes 1-10 as shown below.
Throughout the schemes, methods will be illustrated wherein R1 is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R1 substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated wherein R4, R6, R7, R8, R9 and R10 are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, unless otherwise noted, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated wherein X is xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94. It will be understood by those skilled in the art that other X groups can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
As shown in Scheme 1, reaction of acrolein with an N-protected a-amino acid ester 1 (P1 is an N-protecting group, preferably a benzyl group or the like and P2 is a carboxylic acid protecting group, preferably a t-butyl group or the like) in an inert solvent (for example, toluene and the like) in the presence of an acid catalyst (for example, acetic acid and the like), followed by equilibration with a base (for example, with triethylamine or the like) and separation of the isomers by chromatography, provides substituted pyrrolidine 2. Reduction of the aldehyde group to an alcohol with an aldehyde to alcohol reducing agent (for example, sodium borohydride or the like) in an inert solvent (for example, methanol or the like), followed by chromatographic separation of the isomers provides alcohol 3. Alcohol 3 can be protected with an hydroxy protecting group P3 (preferably with a silyl protecting group, for example, t-butyldimethylsilyl or the like) using standard alcohol protection methods to provide 4. Oxidation of the vinyl group of compound 4 to an aldehyde is accomplished by reacting compound 4 with OsO4 and N-methylmorpholine N-oxide to give the corresponding diol. The diol is then treated with sodium periodate to provide aldehyde 5. Substituents R3 can be introduced via reaction of aldehyde 5 with a Grignard reagent (for example, R3MgBr or the like) to give alcohol 6. Oxidation of alcohol 6 (for example, Swern oxidation or the like) provides ketone 7. Reductive amination of ketone 7 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 8. Amine 8 can be further functionalized to complete the introduction of the R2xe2x80x94Xxe2x80x94 substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 9a. The other diastereomeric amine (9b) can also be isolated and further transformed according to Scheme 1.
Removal of hydroxy protecting group P3 (for example, by reaction with a fluoride ion source, such as tetrabutylammonium fluoride or the like, when P3 is a silyl protecting group) provides alcohol 10. Transformation of the hydroxy group of alcohol 10 allows introduction of various substituents Y.
For example, alkylation of the hydroxy group provides ethers 11. N-deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 12xe2x80x2, followed by ester hydrolysis (for example, with acid such as HCl), provides compound 12xe2x80x3 of the invention.
Oxidation of the hydroxy group of 10 (for example, Swern oxidation or the like) provides aldehyde 13. Oxidation of aldehyde 13 (for example, with NaClO2 or the like) provides carboxylic acid 14. The carboxylic acid substituent of 14 can be used to introduce a variety of other functional groups in substituent Y. For example, the carboxylic acid can be esterified (for example, by reaction with diazomethane or with ethanol and DCC or the like) or the carboxylic acid or an activated derivative thereof can be reacted with amines to provide 15 (wherein xe2x80x94C(xe2x95x90O)xe2x80x94R22 represents an ester or an amide). N-deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 16xe2x80x2, followed by ester hydrolysis (for example, with acid such as HCl), provides compound 16xe2x80x3 of the invention.
Derivatives of the aldehyde group of 13 or the carboxylic acid group of 14 can be used to introduce substituents Y which are xe2x80x94CN or various heterocycles, according to methods known to those skilled in the art and according to the specific methods exemplified herein.
Reaction of aldehyde 13 with loweralkyl- or loweralkenyl-Grignard reagents, followed by oxidation (for example, Swern oxidation or the like), provides ketones 17 wherein R22 is loweralkyl or loweralkenyl. N-deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 18xe2x80x2, followed by ester hydrolysis (for example, with acid such as HCl), provides compound 18xe2x80x3 of the invention.
Compounds wherein substituent Y is an amino group or a derivative of an amino group can be prepared as shown in Scheme 2. Oxidation of aldehyde 2 (for example, with AgO or NaClO2 or the like) provides carboxylic acid 19. Curtius rearrangement of carboxylic acid 19 (for example, reaction with DPPA, Et3N and benzyl alcohol or the like), followed by chromatographic separation of the diastereomers, provides amide 20 wherein P4 is an N-protecting group (for example, benzyloxycarbonyl or the like). Transformations analogous to those which converted compound 4 to compound 9a and 9b in Scheme 1, enable the conversion of 20 to 21a and 21b, which can be separated by chromatography. Removal of protecting group P4 (for example, by selective hydrogenation) provides 22. Further derivatization of the amino group allows for introduction of substituents Y which are amine derivatives. N-deprotection (for example, where P1 is a benzyl group, by hydrogenation), followed by ester hydrolysis (for example, with acid such as HCl), provides compounds of the invention wherein Y is amino or an amine derivative.
Olefination of aldehyde 13 (for example, with Ph3PCH2 or the like), followed by hydrogenation (causing N-deprotection (for example, where P1 is a benzyl group) and olefin saturation, followed by ester hydrolysis (for example, with acid such as HCl), provides compounds of the invention wherein Y is loweralkyl.
As shown in Scheme 3, oxidation of the vinyl group of compound 4 to a diol (for example, with OsO4 and N-methylmorpholine N-oxide or the like) gives diol 23. Removal of N-protecting group P1 (for example, where P1 is a benzyl group, by hydrogenation) provides pyrrolidine 24. Reprotection with an acid-labile N-protecting group P5 (for example, t-butoxycarbonyl or the like) provides 25. Transformation of compound 25 to aldehyde 26a and 26b can be accomplished in a manner analogous to conversion of compound 4a to compound 10 and compound 10 to compound 13 as shown in Scheme 1. 26a and 26b can be separated by chromatography.
Olefination of 26a (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or Ixe2x88x92Ph3P+CH2CH3/KOtBu, or the like) provides 27 wherein Y is an olefinic substituent. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 28 wherein Y is an olefinic substituent.
In yet another alternative method shown in Scheme 4, the hydroxy group of alcohol 3 is protected with a base-labile hydroxy protecting group P6 (for example, acetyl or the like) to give compound 29. Oxidation of the vinyl group of 29 with OsO4 and N-methylmorpholine N-oxide provides diol 30. Removal of the P1 protecting group (for example, by hydrogenation or the like) provides pyrrolidine 31. Reprotection with an acid-labile N-protecting group P5 (for example, t-butoxycarbonyl or the like) provides 32. Selective protection of the primary alcohol of 32 with a hydroxy protecting group P7 (for example, a silyl protecting group such as triisopropylsilyl or the like) provides compound 33. Oxidation of 33 (for example, Swern oxidation or the like) provides ketone 34. Reductive amination of ketone 34 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 35. Amine 35 can be further functionalized to complete the introduction of the R2xe2x80x94Xxe2x80x94 substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 36a. The other diastereomeric amine (36b) can also be isolated and further transformed according this scheme.
Selective removal of the P6 hydroxy protecting group in 36a (for example, with K2CO3 in methanol or the like) provides alcohol 37. Oxidation of the alcohol to an aldehyde (for example, Swern oxidation or the like) provides 38. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 38 (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or Ixe2x88x92Ph3P+CH2CH3/KOtBu, or the like) provides 39 wherein Y is an olefinic substituent. Removal of the P7 hydroxy protecting group (for example, with a fluoride ion source such as tetrabutylammonium fluoride or the like) gives alcohol 40.
The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the alcohol of 40 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 41. Aldehyde 41 can be reacted with Grignard reagents (R14MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R14Li or the like) to provide 42 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 42a and the other isomer 42b. Isomer 42a or the mixture of isomers 42 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 43. Reduction of ketone 43 (for example, with sodium borohydride in ethanol or the like) provides alcohol 42b as the major isomer, which can be isolated by chromatography. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 44a or 44b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 42a or 42b provides ethers 45a or 45b, respectively. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 48a or 48b, respectively, wherein Y is an olefinic substituent.
As shown in Scheme 5, reaction of ketone 43 with Grignard reagents (R37aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R37aLi or the like) provides alcohols 46a and 46b as a mixture of alcohol diastereomers which can be separated chromatographically. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 47a or 47b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 46a or 46b provides ethers 49a or 49b, respectively. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 50a or 50b, respectively, wherein Y is an olefinic substituent.
Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
Scheme 6 illustrates a method for preparing enantiomerically enriched compounds of the invention having the preferred absolute stereochemistry. Protected pyrrole 51 (wherein P8 is an N-protecting group, for example, t-butyloxycarbonyl or the like, and P9 is a hydroxy protecting group, for example, t-butyldimethylsilyl or the like; J. Org. Chem. 57 3760-3763 (1992)) is reacted with imine 52 (wherein P10 is an N-protecting group, for example, p-toluenesulfinyl (xe2x80x94S(O)Tol), t-butylsulfinyl (xe2x80x94S(O)-t-Bu), tritylsulfenyl ((Ph)3Cxe2x80x94Sxe2x80x94), phenylsulfenyl (Ph-Sxe2x80x94), p-methoxyphenyl, p-methoxybenzyl or the like and wherein any functional groups within group R3 that require protection are appropriately protected) in the presence of a Lewis acid, for example, trimethylsilyltriflate, borontrifluoride etherate or the like, in an inert solvent, for example, dichloromethane or the like, to provide unsaturated lactam 53 Preferably, N-protecting groups P8 and P10 can be selectively deprotected/removed in the presence of each other. Reaction of 53 with an organometallic reagent Yxe2x80x94M (wherein M is a metal), for example, a cuprate reagent or the like, in an inert solvent, for example, THF or the like, provides substituted lactam 54. Lactam 54 is converted to cyano-substituted pyrrolidine 55, for example, by (i) reduction with a lactam reducing agent, for example, diisobutylaluminum hydride or the like, in an inert solvent, for example, THF or the like, followed by (ii) treatment with methanol and a catalytic amount of an acid, for example, pyridinium p-toluenesulfonic acid or the like, followed by (iii) reaction with a cyanide source, for example, trimethylsilylcyanide or the like, in an inert solvent, for example, dichloromethane or the like. Alternatively, lactam 54 is converted to cyano-substituted pyrrolidine 55, for example, by (i) reduction with a lactam reducing agent, for example, diisobutylaluminum hydride or the like, in an inert solvent, for example, THF or the like, followed by (ii) reaction with a cyanide source, for example, trimethylsilylcyanide or the like, in an inert solvent, for example, dichloromethane or the like in the presence of a Lewis acid such as trimethylsilyl triflate or the like. Removal of protecting group P10 (for example, with an acid such as trifluoroacetic acid, pyridinium p-toluenesulfonic acid or the like in a suitable solvent), followed by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods gives 56. Hydrolysis of the nitrile of 56 and removal of protecting group P8, for example, with hydrochloric acid or the like, and deprotection of any protected functional groups within group R3 provides carboxylic acid 57. Esters or prodrugs of 57 can be prepared by methods known in the art.
Among the preferred compounds of the invention are compounds such as 58 or esters or prodrugs thereof wherein R37a, R37c and R14 are as defined most broadly herein. Especially preferred are compounds 58 or esters or prodrugs thereof wherein R37a is loweralkyl or loweralkenyl, R37c is hydrogen, C1-C3 loweralkyl or allyl and R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl. In those cases where R37c is hydrogen, the hydroxy group will be protected throughout the process of Scheme 6. Compound 58 can be prepared according to the process described in Scheme 6 by first reacting 51 with imine 59.
The N-protected imine 52 is prepared by reaction of the corresponding aldehyde with P10NH2.
Scheme 7 illustrates a method for preparing preferred imines 59. Allylic alcohol 60 (wherein R14a and the carbon to which it is bonded, when taken together, will become substituent R14) is asymmetrically epoxidized, for example, by Sharpless epoxidation with t-butyl hydroperoxide, (xe2x88x92)-dimethyl D-tartrate and titanium tetraisopropoxide or the like in an inert solvent such as dichloromethane and the like and the alcohol is protected (for example, P11 is benzoate or the like) to give 61. Epoxide 61 is reduced, for example, with lithium aluminum hydride or the like in an inert solvent such as THF or the like, followed by protection of the primary alcohol of 62 (for example, P12 is benzyl or the like) to give 63. Where R37c is other than hydrogen, 63 is reacted with a non-nucleophilic strong base, for example, sodium bis(trimethylsilyl)amide or the like, and R37cxe2x80x94X wherein X is a halide or other leaving group in an inert solvent such as THF or the like to provide 64. Where R37c is hydrogen, the hydroxy group is protected. Protecting group P12 is removed, preferably, selectively if any other hydroxy protecting groups are present in the compound, for example, by hydrogenation when it is a benzyl group, and the resulting alcohol is oxidized to an aldehyde, for example, with pyridinium chlorochromate or the like to give aldehyde 65. Reaction of 65 with P10NH2 gives 59.
An alternative method for preparation of enantiomerically enriched compounds of the invention having the preferred absolute stereochemistry is shown in Scheme 8. Unsaturated lactam 66 (Tetrahedron Asymmetry 1167-1180 (1996)) wherein P13 is an N-protecting group, for example, t-butyloxycarbonyl or the like, and P14 is a hydroxy protecting group, for example, t-butyldimethylsilyl or the like, is reacted with an organometallic reagent Yxe2x80x94M (wherein M is a metal), for example, a cuprate reagent or the like, in an inert solvent, for example, THF or the like, to provide 67. Lactam 67 is converted to cyano-substituted pyrrolidine 68, for example, by (i) reduction with a lactam reducing agent, for example, diisobutylaluminum hydride or the like, in an inert solvent, for example, THF or the like, followed by (ii) treatment with methanol and a catalytic amount of an acid, for example, pyridinium p-toluenesulfonic acid or the like, followed by (iii) reaction with a cyanide source, for example, trimethylsilylcyanide or the like, in an inert solvent, for example, dichloromethane or the like. Deprotection of the alcohol (for example, with a fluoride ion source such as tetrabutylammonium fluoride or the like when P14 is a silyl based hydroxy protecting group), followed by conversion of the alcohol to an azide group (for example, by reaction with triphenylphosphine, diethyl diazodicarboxylate and diphenylphosphory azide or the like in an inert solvent such as THF or the like) provides 69. The azide is reduced (for example, with triphenylphosphine in THF/water or the like), the resulting amine is acylated (for example, with an acylating agent such as acetic anhydride or the like or by other acylation methods) and the diol is deprotected (for example, with acetic acid or the like) to give 70. Diol 70 is oxidized to the aldehyde 71, for example, with sodium metaperiodate or the like. The aldehyde 71 can be converted to 72 by methods described in Schemes 4 and 5. Compound 72 can be converted to 57 according to the method described in Scheme 6 for converting 56 to 57.
More particularly, compounds 58 wherein R37a is loweralkyl or loweralkenyl, R37c is hydrogen, C1-C3 loweralkyl or allyl and R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl are prepared from 71 according to the methods outlined in Schemes 4 and 5 to give 73, which is converted to 58. In those cases where R37c is hydrogen, the hydroxy group will be protected throughout the process of Scheme 8.
Another alternative method for preparation of enantiomerically enriched compounds of the invention having the preferred absolute stereochemistry is shown in Scheme 9. Aldehyde 74 (wherein P15 is an N-protecting group, for example, t-butyloxycarbonyl or the like and, preferably, wherein R37a is loweralkyl or loweralkenyl, R37c is hydrogen, C1-C3 loweralkyl or allyl and R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl) is reacted with N-protected hydroxylamine P16xe2x80x94NHOH wherein P16 is an N-protecting group, for example, p-methoxybenzyl or the like, to provide nitrone 75. Preferably, N-protecting groups P15 and P16 can be selectively deprotected/removed in the presence of each other. The carbanion of a carboxy protected propiolate is prepared by reacting the carboxy protected propiolate (P17 is an acid protecting group, for example, methyl or t-butyl or the like) with a non-nucleophilic strong base, for example, n-BuLi or the like in an inert solvent, for example, THF or the like. The propiolate carbanion is then reacted with nitrone 75 to give 76. Reaction of 76 with zinc dust in acetic acid/methanol provides unsaturated lactam 77. Unsaturated lactam 77 is reacted with an organometallic reagent Yxe2x80x94M (wherein M is a metal), for example, a cuprate reagent or the like, in an inert solvent, for example, THF or the like, to provide 78. Removal of protecting group P15 (for example, with an acid such as trifluoroacetic acid, pyridinium p-toluenesulfonic acid or the like in a suitable solvent), followed by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods gives 79. Optionally, N-protecting group P16 can be replaced by another N-protecting group before completing the process (for example, where P16 is p-methoxybenzyl or the like it can be removed and replaced with t-butyloxycarbonyl or the like). Lactam 79 is converted to cyano-substituted pyrrolidine 80, for example, by (i) reduction with a lactam reducing agent, for example, diisobutylaluminum hydride or the like, in an inert solvent, for example, THF or the like, followed by (ii) treatment with methanol and a catalytic amount of an acid, for example, pyridinium p-toluenesulfonic acid or the like, followed by (iii) reaction with a cyanide source, for example, trimethylsilylcyanide or the like, in an inert solvent, for example, dichloromethane or the like. Hydrolysis of the nitrile of 80 and removal of protecting group P16, for example, with hydrochloric acid or the like, provides carboxylic acid 58. In those cases where R37c is hydrogen, the hydroxy group will be protected throughout the process of Scheme 9. Esters or prodrugs of 58 can be prepared by methods known in the art.
Compound 74 can be prepared according to the process shown in Scheme 10. In Scheme 10, P15 is exemplified by t-butyloxycarbonyl (Boc), but can be other N-protecting groups. Compound 81 is prepared from D-serine according to Campbell, et al., Synthesis 1707 (1998). Reaction of 81 with an organometallic reagent R14xe2x80x94M wherein M is a metal (for example, a Grignard reagent (R14xe2x80x94MgCl or R14xe2x80x94MgBr or the like) in an inert solvent, for example, THF or the like, provides 82. Ketone 82 is reacted with an organometallic reagent R37axe2x80x94M wherein M is a metal (for example, a Grignard reagent, R37axe2x80x94MgCl or R37axe2x80x94MgBr or the like) in an inert solvent, for example, THF or the like, to provide 83, where R37c is other than hydrogen, 83 is reacted with a non-nucleophilic strong base (for example, sodium hydride or the like) in an inert solvent such as THF or the like, followed by reaction with R37cxe2x80x94X where X is a leaving group such as a halide or the like to provide 84. Where R37c is hydrogen, the hydroxy group is suitably protected. Deprotection of 84, for example, with p-toluenesulfonic acid in methanol or the like, provides 85. Oxidation of 85, for example, with pyridine sulfur trioxide complex, DMSO and pyridine or the like, gives aldehyde 86, which corresponds to 74 wherein P15 is t-butyloxycarbonyl. 
The other compounds of the invention can be readily prepared from the compounds described herein using techniques known in the chemical literature. The methods required are known and can be readily practiced by those having ordinary skill in the art.
Key intermediates for the preparation of compounds of the invention include the following. 
wherein P1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferrably, a loweralkyl group, especially t-butyl); preferrably, P1 and P2 can be selectively deprotected/removed; or a salt thereof; 
wherein P1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P3 is hydrogen or a hydroxy protecting group (preferably, an acyl protecting group, for example, acetyl and the like, or a silyl protecting group, for example, t-butyldimethylsilyl and the like); preferrably, P1, P2 and P3 can be selectively deprotected/removed; or a salt thereof; 
wherein P1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P4 is hydrogen or an N-protecting group (preferably, a carbamate N-protecting group, for example, benzyloxycarbonyl and the like); preferrably, P1, P2 and P4 can be selectively deprotected/removed; or a salt thereof; 
wherein P5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); preferrably, P2, P5, P6 and P7 can be selectively deprotected/removed; or a salt thereof; and 
wherein P5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); and R2 is defined as herein (preferably, loweralkyl or haloloweralkyl; most preferably, methyl or trifluoromethyl); preferrably, P2, P5, P6 and P7 can be selectively deprotected/removed; or a salt thereof.
Other key intermediates for the preparation of compounds of the invention include compounds, including mixtures of compounds having the indicated relative stereochemistry or enantiomerically enriched compounds having the indicated absolute stereochemistry, of the formula (6)-(17). 
wherein P8 is an N-protecting group (including, t-butyloxycarbonyl or the like), P10 is an N-protecting group (including, p-toluenesulfinyl (xe2x80x94S(O)Tol), t-butylsulfinyl (xe2x80x94S(O)-t-Bu), tritylsulfenyl ((Ph)3Cxe2x80x94Sxe2x80x94), phenylsulfenyl (Ph-Sxe2x80x94), p-methoxyphenyl, p-methoxybenzyl or the like) and R3 is defined as above (both in terms of its broadest definition and in terms of each of the preferred embodiments); or a salt thereof. In addition, any functional groups in substituent R3 can be suitably protected. Most highly preferred is substituent R3 of the formula: 
wherein R37a, R37c and R14 are as defined above (both in terms of their broadest definitions and in terms of each of their preferred embodiments). Especially preferred are compounds wherein R37, is loweralkyl or loweralkenyl, R37c is hydrogen, C1-C3 loweralkyl or allyl and R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl. In those cases where R37c is hydrogen, the hydroxy group can be protected with a hydroxy protecting group. Preferably, P8 and P10 can be selectively deprotected/removed. 
wherein P8, P10 and R3 are defined as in (6) above and wherein Y is defined as above (both in terms of its broadest definition and in terms of each of the preferred embodiments); or a salt thereof. 
wherein P8, P10, R3 and Y are defined as in (7) above; or a salt thereof. 
wherein P8, R3 and Y are defined as in (7) above and R2 is defined as above (both in terms of its broadest definition and in terms of each of the preferred embodiments); or a salt thereof. 
wherein P10, R14, R37a and R37c are as defined in (6) above; or a salt thereof. 
wherein R14, R37a and R37c are as defined in (6) above; or a salt thereof. 
wherein R14, R37a and R37c are as defined in (6) above, R2 is as defined in (9) above and P13 is an N-protecting group (including, t-butyloxycarbonyl or the like); or a salt thereof. 
wherein R14, R37a and R37c are as defined in (6) above and P15 is an N-protecting group (including, t-butyloxycarbonyl or the like); or a salt thereof. 
wherein R14, R37a, R37c and P15 are as defined in (13) above and P16 is an N-protecting group (including, p-methoxybenzyl or the like): or a salt thereof. Preferably, P15 and P16 can be selectively deprotected/removed. 
wherein R14, R37a, R37c P15 and P16 are as defined in (14) above and P17 is an acid protecting group (including, methyl or t-butyl or the like); or a salt thereof. 
wherein R14, R37a, R37c and P16 are as defined in (14) above and R2 is as defined in (9) above; or a salt thereof. 
wherein R14, R37a, R37c, P16 and R2 are as defined in (16) above; or a salt thereof.
The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA); Alfa Aesar (Ward Hill, Mass. 01835-9953); Eastman Chemical Company (Rochester, N.Y. 14652-3512); Lancaster Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 08901); Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
The following examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.